Search

Introduction: Evaluating the generalizability of dementia risk scores, primarily developed in non-Latinx White (NLW) participants, and interactions with genetic risk factors in diverse populations is crucial for addressing health disparities., Methods: We analyzed the association of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) and modified CAIDE (mCAIDE) scores with dementia risk using logistic regression models stratified by race/ethnicity in National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), and assessed their interaction with apolipoprotein E (APOE)., Results: Higher CAIDE scores were associated with an increased risk of dementia in Asian, Latinx, and NLW participants but not in Black participants. In contrast, higher mCAIDE scores were also associated with an increased risk of dementia in Black participants. Unfavorable mCAIDE risk profiles exacerbated the apolipoprotein E*ε4 (APOE*ε4) risk effect and attenuated the APOE*ε2 protective effect., Discussion: Our findings underscore the importance of evaluating the validity of dementia risk scores in diverse populations for their use in personalized medicine approaches to promote brain health., Highlights: Dementia risk scores demonstrate race/ethnic-specific effects on dementia risk. Unfavorable modifiable risk profiles moderate the effect of APOE on dementia risk. Dementia risk scores need to be validated in diverse populations., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Education is strongly associated with cognitive outcomes at older ages, yet the extent to which these associations reflect causal effects remains uncertain due to potential confounding., Methods: Leveraging changes in historical measures of state-level education policies as natural experiments, we estimated the effects of educational attainment on cognitive performance over 10 years in 20,248 non-Hispanic Black and non-Hispanic White participants, aged 45+ in the REasons for Geographic and Racial Disparities in Stroke (REGARDS) cohort (2003-2020) by (1) using state- and year- specific compulsory schooling laws, school-term length, attendance rate, and student-teacher ratio policies to predict educational attainment for US Census microsample data from 1980 and 1990, and (2) applying policy-predicted years of education (PPYEd) to predict memory, verbal fluency, and a cognitive composite. We estimated overall and race- and sex-specific effects of PPYEd on level and change in each cognitive outcome using random intercept and slope models, adjusting for age, year of first cognitive assessment, and indicators for state of residence at age 6., Results: Each year of PPYEd was associated with higher baseline cognition (0.11 standard deviation [SD] increase in composite measure for each year of PPYEd, 95% confidence interval [CI]: 0.07, 0.15). Subanalyses focusing on individual cognitive domains estimate the largest effects of PPYEd on memory. PPYEd was not associated with rate of change in cognitive scores. Estimates were similar across Black and White participants and across sex., Conclusions: Historical policies shaping educational attainment are associated with better later life memory, a major determinant of dementia risk., Competing Interests: Conflict of Interest: None declared, (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Evaluating the generalizability of dementia risk scores, primarily developed in non-Latinx White (NLW) participants, and interactions with genetic risk factors in diverse populations is crucial for addressing health disparities., Methods: We analyzed the association of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) and modified CAIDE (mCAIDE) scores with dementia risk using logistic regression models stratified by race/ethnicity in NACC and ADNI, and assessed their interaction with APOE ., Results: Higher CAIDE scores were associated with an increased risk of dementia in Asian, Latinx, and NLW participants but not in Black participants. In contrast, higher mCAIDE scores were also associated with an increased risk of dementia in Black participants. Unfavorable mCAIDE risk profiles exacerbated the APOE *ε4 risk effect and attenuated the APOE *ε2 protective effect., Discussion: Our findings underscore the importance of evaluating the validity of dementia risk scores in diverse populations for their use in personalized medicine approaches to promote brain health., Competing Interests: Conflict of Interest Disclosures The authors report no conflicts of interest.

Importance: Vision and eye conditions are associated with increased risk for Alzheimer disease and related dementias (ADRDs), but the nature of the association and the underlying biological pathways remain unclear. If causal, vision would be an important modifiable risk factor with viable population-level interventions., Objective: To evaluate potentially causal associations between visual acuity, eye conditions (specifically cataracts and myopia), neuroimaging outcomes, and ADRDs., Design, Setting, and Participants: A cohort and 2-sample bidirectional mendelian randomization (MR) study was conducted using UK Biobank participants and summary statistics from previously published genome-wide association studies on cataract, myopia, and AD. The participants included in the analysis were aged 55 to 70 years without dementia at baseline (calendar years 2006 to 2010), underwent genotyping, and reported on eye conditions; a subset completed visual acuity examinations (n = 69 852-71 429) or brain imaging (n = 36 591-36 855). Data were analyzed from August 15, 2022, through November 28, 2023., Exposure: Self-reported cataracts, visual acuity, and myopia measured by refraction error., Main Outcomes and Measures: ADRD, AD, and vascular dementia were identified from electronic medical records. Total and regional brain volumes were determined using magnetic resonance imaging., Results: The sample included 304 953 participants (mean [SD] age, 62.1 (4.1) years; 163 825 women [53.72%]); 14 295 (4.69%) had cataracts and 2754 (3.86%) had worse than 20/40 vision. Cataracts (hazard ratio [HR], 1.18; 95% CI, 1.07-1.29) and myopia (HR, 1.35; 95% CI, 1.06-1.70) were associated with a higher hazard of ADRD. In MR analyses to estimate potential causal effects, cataracts were associated with increased risk of vascular dementia (inverse variance-weighted odds ratio [OR], 1.92; 95% CI, 1.26-2.92) but were not associated with increased dementia (OR, 1.21; 95% CI, 0.98-1.50). There were no associations between myopia and dementia. In MR for potential reverse causality, AD was not associated with cataracts (inverse variance-weighted OR, 0.99; 95% CI, 0.96-1.01). Genetic risk for cataracts was associated with smaller total brain (β = -597.43 mm3; 95% CI, -1077.87 to -117.00 mm3) and gray matter (β = -375.17 mm3; 95% CI, -680.10 to -70.24 mm3) volumes, but not other brain regions., Conclusions and Relevance: In this cohort and MR study of UK Biobank participants, cataracts were associated with increased risk of dementia, especially vascular dementia, and reduced total brain volumes. These findings lend further support to the hypothesis that cataract extraction may reduce the risk for dementia.

Study Objectives: The association between snoring, a very common condition that increases with age, and dementia risk is controversial. We aimed to investigate the observational and causal relationship between snoring and dementia, and to elucidate the role of body mass index (BMI)., Methods: Using data from 451,250 participants who were dementia-free at baseline, we examined the association between self-reported snoring and incident dementia using Cox proportional-hazards models. Causal relationship between snoring and Alzheimer's disease (AD) was examined using bidirectional two-sample Mendelian randomization (MR) analysis., Results: During a median follow-up of 13.6 years, 8,325 individuals developed dementia. Snoring was associated with a lower risk of all-cause dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.89 to 0.98) and AD (HR 0.91; 95% CI 0.84 to 0.97). The association was slightly attenuated after adjusting for BMI, and was stronger in older individuals, APOE ε4 allele carriers, and during shorter follow-up periods. MR analyses suggested no causal effect of snoring on AD, however, genetic liability to AD was associated with a lower risk of snoring. Multivariable MR indicated that the effect of AD on snoring was primarily driven by BMI., Conclusions: The phenotypic association between snoring and lower dementia risk likely stems from reverse causation, with genetic predisposition to AD associated with reduced snoring. This may be driven by weight loss in prodromal AD. Increased attention should be paid to reduced snoring and weight loss in older adults as potential early indicators of dementia risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: We estimated the ages when associations between Alzheimer's disease (AD) genes and brain volumes begin among middle-aged and older adults., Methods: Among 45,616 dementia-free participants aged 45-80, linear regressions tested whether genetic risk score for AD (AD-GRS) had age-dependent associations with 38 regional brain magnetic resonance imaging volumes. Models were adjusted for sex, assessment center, genetic ancestry, and intracranial volume., Results: AD-GRS modified the estimated effect of age (per decade) on the amygdala (-0.41 mm 3 [-0.42, -0.40]); hippocampus (-0.45 mm 3 [-0.45, -0.44]), nucleus accumbens (-0.55 mm 3 [-0.56, -0.54]), thalamus (-0.38 mm 3 [-0.39, -0.37]), and medial orbitofrontal cortex (-0.23 mm 3 [-0.24, -0.22]). Trends began by age 45 for the nucleus accumbens and thalamus, 48 for the hippocampus, 51 for the amygdala, and 53 for the medial orbitofrontal cortex. An AD-GRS excluding apolipoprotein E (APOE) was additionally associated with entorhinal and middle temporal cortices., Discussion: APOE and other genes that increase AD risk predict lower hippocampal and other brain volumes by middle age., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: We examined the relationship between baseline olfactory performance and incident significant depressive symptoms and longitudinal depression trajectories in well-functioning older adults. Inflammation and cognitive status were examined as potential mediators., Methods: Older adults (n = 2 125, 71-82 years, 51% female, 37% Black) completed an odor identification task at Year 3 (our study baseline) of the Health, Aging, and Body Composition study. Cognitive assessments, depressive symptoms, and inflammatory markers were ascertained across multiple visits over 8 years. Discrete-time complementary log-log models, group-based trajectory models, and multivariable-adjusted multinomial logistic regression were employed to assess the relationship between baseline olfaction and incident depression and longitudinal depression trajectories. Mediation analysis assessed the influence of cognitive status on these relationships., Results: Individuals with lower olfaction had an increased risk of developing significant depressive symptoms at follow-up (hazard ratio = 1.04, 95% confidence interval [CI]: 1.00, 1.08). Of the 3 patterns of longitudinal depression scores identified (stable low, stable moderate, and stable high), poorer olfaction was associated with a 6% higher risk of membership in the stable moderate (relative risk ratio [RRR] = 1.06, 95% CI: 1.02, 1.10)/stable high (RRR = 1.06, 95% CI: 1.00, 1.12) groups, compared to the stable low group. Poor cognitive status, but not inflammation, partially mediated the relationship between olfactory performance and incident depression symptom severity., Conclusions: Suboptimal olfaction could serve as a prognostic indicator of vulnerability for the development of late-life depression. These findings underscore the need for a greater understanding of olfaction in late-life depression and the demographic, cognitive, and biological factors that influence these relationships over time., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Despite existing federal programs to increase access to food, food insecurity is common among US older adults. Food insecurity may affect Alzheimer disease and Alzheimer disease-related dementias via multiple mechanisms, yet there is almost no quantitative research evaluating this association., Objective: To examine whether food insecurity in older adults is associated with later-life cognitive outcomes., Design, Setting, and Participants: This cohort study of US residents aged 50 years and older from the US Health and Retirement Study was restricted to respondents with food insecurity data in 2013 and cognitive outcome data between calendar years 2014 and 2018. Analyses were conducted from June 1 to September 22, 2023., Exposure: Food insecurity status in 2013 was assessed using the validated US Department of Agriculture 6-item Household Food Security Module. Respondents were classified as being food secure, low food secure, and very low food secure., Main Outcomes and Measures: Outcomes were dementia probability and memory score (standardized to 1998 units), estimated biennially between 2014 and 2018 using a previously validated algorithm. Generalized estimation equations were fit for dementia risk and linear mixed-effects models for memory score, taking selective attrition into account through inverse probability of censoring weights., Results: The sample consisted of 7012 participants (18 356 person-waves); mean (SD) age was 67.7 (10.0) years, 4131 (58.9%) were women, 1136 (16.2%) were non-Hispanic Black, 4849 (69.2%) were non-Hispanic White, and mean (SD) duration of schooling was 13.0 (3.0) years. Compared with food-secure older adults, experiencing low food security was associated with higher odds of dementia (odds ratio, 1.38; 95% CI, 1.15-1.67) as was experiencing very low food security (odds ratio, 1.37; 95% CI, 1.11-1.59). Low and very low food security was also associated with lower memory levels and faster age-related memory decline., Conclusions and Relevance: In this cohort study of older US residents, food insecurity was associated with increased dementia risk, poorer memory function, and faster memory decline. Future studies are needed to examine whether addressing food insecurity may benefit brain health.

Introduction: Middle-aged and older adults who develop cancer experience memory loss following diagnosis, but memory decline in the years before and after cancer diagnosis is slower compared to their cancer-free counterparts. Educational attainment strongly predicts memory function during aging, but it is unclear whether education protects against memory loss related to cancer incidence or modifies long-term memory trajectories in middle-aged and older cancer survivors., Materials and Methods: Data were from 14,449 adults (3,248 with incident cancer, excluding non-melanoma skin cancer) aged 50+ in the population-based US Health and Retirement Study from 1998 to 2016. Memory was assessed every two years as a composite of immediate and delayed word recall tests and proxy assessments for impaired individuals. Memory scores all time points were standardized at to the baseline distribution. Using multivariate-adjusted linear mixed-effects models, we estimated rates of memory decline in the years before cancer diagnosis, shortly after diagnosis, and in the years after diagnosis. We compared rates of memory decline between incident cancer cases and age-matched cancer-free adults, overall and according to level of education (<12 years, "low"; 12 to <16 years, "intermediate"; ≥16 years, "high")., Results: Incident cancer diagnoses were followed by short-term declines in memory averaging 0.06 standard deviation (SD) units (95% confidence interval [CI]: -0.084, -0.036). Those with low education experienced the strongest magnitude of short-term decline in memory after diagnosis (-0.10 SD units, 95% CI: -0.15, -0.05), but this estimate was not statistically significantly different from the short-term decline in memory experienced by those with high education (-0.04 SD units, 95% CI: -0.08, 0.01; p-value for education as an effect modifier = 0.15). In the years prior to and following an incident cancer diagnosis, higher educational attainment was associated with better memory, but it did not modify the difference in rate of long-term memory decline between cancer survivors and those who remained cancer-free., Discussion: Education was associated with better memory function over time among both cancer survivors and cancer-free adults aged 50 and over. Low education may be associated with a stronger short-term decline in memory after a cancer diagnosis., Competing Interests: Declaration of Competing Interest None reported., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We examined associations of an Alzheimer's disease (AD) Genetic Risk Score (AD-GRS) and midlife cognitive and neuroimaging outcomes in 1,252 middle-aged participants (311 with brain MRI). A higher AD-GRS based on 25 previously identified loci (excluding apolipoprotein E [APOE]) was associated with worse Montreal Cognitive Assessment (-0.14 standard deviation [SD] [95% confidence interval {CI}: -0.26, -0.02]), older machine learning predicted brain age (2.35 years[95%CI: 0.01, 4.69]), and white matter hyperintensity volume (0.35 SD [95% CI: 0.00, 0.71]), but not with a composite cognitive outcome, total brain, or hippocampal volume. APOE ε4 allele was not associated with any outcomes. AD risk genes beyond APOE may contribute to subclinical differences in cognition and brain health in midlife. ANN NEUROL 2023;93:629-634., (© 2022 American Neurological Association.)

Recent high-profile failures of Alzheimer disease treatments at the clinical trial stage have led to renewed efforts to identify and test novel interventions for Alzheimer disease and related dementias (ADRD). In this Perspective, we highlight the importance of including well-designed observational studies as part of these efforts. Observational research is an important cornerstone for gathering evidence on risk factors and causes of ADRD; this evidence can then be combined with data from preclinical studies and randomized controlled trials to inform the development of effective interventions. Observational study designs can be particularly beneficial for hypothesis generation, posing questions that are unethical or impractical for a trial setting, studying life-course associations, research in populations typically not included in trials, and public health surveillance. Here, we discuss each of these situations in the specific context of ADRD research. We also highlight novel approaches to enhance causal inference and provide a timely discussion on how observational epidemiological studies help provide a bridge between preclinical studies and successful interventions for ADRD., (© 2022. Springer Nature Limited.)

Objective: We explored the associations of dual sensory impairment (DSI) with long-term depressive and anxiety symptoms as well as low perceived social support (LPSS) as a modifier of these associations., Methods: Multinomial logistic regression models were used to examine the associations of DSI and single sensory impairment (hearing [pure-tone average > 25 dB] and vision [impaired visual acuity and/or contrast sensitivity]) with long-term depressive symptom (≥8 on the 10-item Center for Epidemiologic Studies-Depression Scale) and anxiety symptom (present on the Hopkins Symptom Checklist) latent classes from group-based trajectory models (rare/never; mild/moderate increasing; chronically high) among 2102 Health, Aging and Body Composition Study participants (mean age:74.0 ± 2.8 years; 51.9 % female) over 10 years. Models were adjusted by demographic characteristics and cardiovascular risk factors, and LPSS. An additional model evaluated the two-way interaction between DSI and LPSS., Results: DSI was associated with increased risk of being chronically depressed (Risk Ratio, RR = 1.99, 95 % Confidence Interval, CI: 1.25, 3.17), not mild/moderate increasingly depressed (RR = 1.25, 95 % CI: 0.91, 1.71). DSI had increased risk of being mild/moderate increasingly anxious (RR = 1.60, 95 % CI: 1.16, 2.19) and chronically anxious (RR = 1.86, 95 % CI: 1.05, 3.27) groups, as compared to no impairments. Hearing impairment was associated with being mild/moderate increasingly anxious (RR = 1.34, 95 % CI: 1.01, 1.79). No other associations were found for single sensory impairments. LPSS did not modify associations., Limitations: Sensory measures were time-fixed, and LPSS, depression and anxiety measures were self-reported., Conclusions: Future research is warranted to determine if DSI therapies may lessen long-term chronically high depressive and anxiety symptoms., (Copyright © 2022. Published by Elsevier B.V.)

Background: There is a dearth of studies examining the associations of objectively measured dual sensory impairment (DSI) with incident mobility and activities of daily life (ADL) difficulty longitudinally., Methods: Cox proportional hazards models were used to examine the associations of DSI and single sensory impairment (hearing, vision) with incident mobility difficulty (many problems or inability to walk ¼ mile and/or climb 10 steps) and ADL difficulty up to six years of follow-up among 2020 participants of the Health, Aging, and Body Composition Study, a cohort of older adults aged 70-79 years from Pittsburgh, PA and Memphis, TN. Vision impairment (VI) was defined as impaired visual acuity (20/50 or worse on Bailey-Lovie distance test) and contrast sensitivity (<1.3 log units on Pelli-Robson test), and hearing impairment (HI) was defined as pure-tone average in better-hearing ear >25 decibels. Models were adjusted by age, race, sex, education, diabetes, depressive symptoms, hypertension, gait speed from 20-meter walk, global cognition score, prevalent cardiovascular disease, and body mass index., Results: There were 23% with DSI (n = 459). DSI was associated with increased risk of both incident report of mobility (hazard ratio [HR] = 2.25, 95% confidence interval [CI]: 1.47, 3.43), and ADL difficulty (HR = 2.26, 95% CI: 1.50, 3.40). Neither VI nor HI alone was associated with risk of either outcome., Conclusions: DSI is associated with increased risk of incident mobility and ADL difficulty. Rehabilitation and adaptive environmental changes for individuals living with DSI may be important to maximize mobility and daily function., (© 2022 The American Geriatrics Society.)

Introduction: We aimed to investigate bidirectional associations between cognitive impairment and late age-related macular degeneration (AMD)., Methods: Participants in the Age-Related Eye Disease Study 2 (AREDS2) received annual eye examinations and cognitive function testing (e.g., Modified Telephone Interview for Cognitive Status [TICS-M]). We examined bidirectional associations between cognitive impairment (e.g., a TICS-M score < 30) and late AMD at 5 and 10 years., Results: Five thousand one hundred eighty-nine eyes (3157 participants; mean age 72.7 years) were analyzed and followed for a median of 10.4 years. Eyes of participants with cognitive impairment at baseline were more likely to progress to late AMD at 5 years (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.08-1.43) and 10 years (HR, 1.20; 95% CI, 1.05-1.37) than eyes of participants without cognitive impairment. Worse baseline AMD severity was not associated with developing cognitive impairment., Discussion: Cognitive impairment is associated with late AMD progression in AREDS2. Our finding highlights the importance of eyecare for people with cognitive impairment., (© 2021 the Alzheimer's Association.)

Importance: The associations between muscle strength and cognitive outcomes have sparked interest in interventions that increase muscle strength for prevention of dementia, but the associations between muscle strength and cognitive aging are unclear, particularly among middle-aged adults., Objective: To evaluate the association between handgrip strength (HGS) and dementia, reduced cognition, and poorer neuroimaging outcomes in a UK population of middle-aged adults., Design, Setting, and Participants: This cohort study evaluated UK Biobank participants aged 39 to 73 years enrolled from 2006 to 2010 with measured HGS and prospectively followed up for dementia diagnosis. Data were analyzed from October 2021 to April 2022., Exposures: HGS assessed in both hands via dynamometer., Main Outcomes and Measures: Outcomes included cognitive test scores (fluid intelligence and prospective memory), brain magnetic resonance imaging measures (total brain volume, white matter hyperintensity, and hippocampal volume), and incident dementia (all-cause, vascular, and Alzheimer disease [AD] from primary care, hospital, or death records) over a median (IQR) of 11.7 (11.0-12.4) years of follow-up. Mixed-effects linear and logistic regressions and Cox proportional-hazard models were used to estimate associations, stratified by gender and adjusted for covariates. Estimates are presented per 5-kg decrement in HGS. To evaluate reverse causation, we assessed whether a polygenic risk score for AD is associated with HGS., Results: A subsample of 190 406 adult participants in the UK Biobank (mean [SD] age, 56.5 [8.1] years; 102 735 women [54%]) were evaluated. A 5-kg decrement in HGS was associated with lower fluid intelligence scores in men (β, -0.007; 95% CI, -0.010 to -0.003) and women (β, -0.04; 95% CI, -0.05 to -0.04. A 5-kg decrement in HGS was associated with worse odds of correctly responding to a prospective memory task for men (odds ratio, 0.91; 95% CI, 0.90 to 0.92) and women (odds ratio, 0.88; 95% CI, 0.87 to 0.90). A 5-kg decrement in HGS was associated with greater white matter hyperintensity volume in men (β, 92.22; 95% CI, 31.09 to 153.35) and women (β, 83.56; 95% CI, 13.54 to 153.58). A 5-kg decrement in HGS was associated with incident dementia for men (hazard ratio, 1.20; 95% CI, 1.12 to 1.28) and women (hazard ratio, 1.12; 95% CI, 1.00 to 1.26). The AD genetic risk score was not significantly associated with HGS., Conclusions and Relevance: These findings suggest that HGS is associated with measures of neurocognitive brain health among men and women and they add to a growing body of research indicating that interventions designed to increase muscle strength, particularly among middle-aged adults, may hold promise for the maintenance of neurocognitive brain health.

Objectives: Late-life depression is a comorbidity that may co-occur in older adults with hearing loss-each has prevalent and independent modifiable risk factors for dementia., Methods: Using data from 1,820 Health, Aging and Body Composition study participants (74 ± 2.8 years, 38% Black race), we compared the hearing loss-dementia/cognitive decline relationship between those with normal hearing/mild hearing loss and those with moderate or greater hearing loss. Using linear mixed-effects and Cox proportional hazard models, we investigated if the associations between hearing loss and cognitive decline or dementia (Modified Mini-Mental State [3MS] Examination and Digit Symbol Substitution Test [DSST]) differed by the presence or absence of depressive symptoms. Depressive symptoms were defined as Center for Epidemiologic Study-Depression scale 10 ≥10 at one or more visits from Years 1-5. Algorithmic incident dementia was defined using medication use, hospitalizations, and cognitive test scores. Audiometric hearing loss was measured at Year 5 and categorized as normal/mild versus moderate or greater hearing loss., Results: Having both hearing loss and depressive symptoms (vs. having neither) was associated with faster rates of decline in 3MS Examination (β = -0.30; 95% confidence interval [CI]: -0.78, -0.19) and DSST (β = -0.35; 95% CI: -0.67, -0.03) over 10 years of follow-up. Having both hearing loss and depressive symptoms (vs. neither) was associated with increased risk (hazard ratio [HR]: 2.91; 95% CI: 1.59, 5.33 vs. HR: 1.54; 95% CI: 1.10, 2.15 hearing loss only and HR: 2.35; 95% CI: 1.56, 3.53 depressive symptoms only) of incident dementia in multivariable-adjusted Cox proportional hazards models., Discussion: Comorbid conditions among hearing-impaired older adults should be considered and may aid in dementia prevention and management strategies., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Peripheral nerve impairments and dementia are common among older adults and share risk factors. However, few studies have examined whether peripheral nerve function and dementia are associated. We evaluated whether lower extremity peripheral nerve impairments were associated with higher incidence of dementia and whether associations differed by comorbidity subgroups (diabetes, low vitamin B 12 , and APOE ε4 allele carriers)., Methods: We studied Black and White Health, Aging, and Body Composition Study participants 70 to 79 years of age and without dementia at enrollment. Lower extremity sensory and motor peripheral nerve function was measured at year 4 (the analytic baseline of this study). Sensory nerve impairments were measured with monofilament (1.4 g, 10 g) and vibration threshold of the toe. Monofilament insensitivity was defined as unable to detect monofilament (3 of 4 touches), and vibration detection impairment was defined as >130 μm. Fibular motor impairments were defined as <1 mV compound motor action potential (CMAP) amplitude and slow nerve conduction velocity <40 m/s. Incident dementia over the following 11 years was determined from medical records, cognitive scores, and medications. Cox proportional hazard models adjusted for demographics and health conditions assessed associations of nerve impairments with incident dementia., Results: Among 2,174 participants (52% women, 35% Black), 45% could not detect monofilament 1.4 g, 9% could not detect monofilament 10 g, 6% could not feel vibration, 10% had low CMAP amplitude, and 24% had slow conduction velocity. Monofilament 10 g (hazard ratio [HR] 1.35, 95% CI 0.99-1.84) and vibration detection insensitivity (HR 1.73, 95% CI 1.24-2.40) were associated/borderline associated with a higher risk of dementia after covariate adjustment. Estimates were elevated but not significant for monofilament 1.4 g, CMAP amplitude, and conduction velocity ( p > 0.05). Increasing number of peripheral nerve impairments was associated with higher risk of dementia in a graded fashion; for ≥3 impairments, the HR was 2.37 (95% CI 1.29-4.38). In subgroup analyses, effect estimates were generally higher among those with diabetes, low vitamin B 12 , and APOE ε4 allele except for vibration detection., Discussion: Peripheral nerve impairments, especially sensory, were associated with a higher risk of dementia even after adjustment for age and other health factors. These associations may represent a shared susceptibility to nervous system degeneration., (© 2022 American Academy of Neurology.)

Importance: Identifying the youngest age when Alzheimer disease (AD) influences cognition and the earliest affected cognitive domains will improve understanding of the natural history of AD and approaches to early diagnosis., Objective: To evaluate the age at which cognitive differences between individuals with higher compared with lower genetic risk of AD are first apparent and which cognitive assessments show the earliest difference., Design, Setting, and Participants: This cross-sectional study used data from UK Biobank participants of European genetic ancestry, aged 40 years or older, who contributed genotypic and cognitive test data from January 1, 2006, to December 31, 2015. Data analysis was performed from March 10, 2020, to January 4, 2022., Exposure: The AD genetic risk score (GRS), which is a weighted sum of 23 single-nucleotide variations., Main Outcomes and Measures: Seven cognitive tests were administered via touchscreen at in-person visits or online. Cognitive domains assessed included fluid intelligence, episodic memory, processing speed, executive functioning, and prospective memory. Multiple cognitive measures were derived from some tests, yielding 32 separate measures. Interactions between age and AD-GRS for each of the 32 cognitive measures were tested with linear regression using a Bonferroni-corrected P value threshold. For cognitive measures with significant evidence of age by AD-GRS interaction, the youngest age of interaction was assessed with new regression models, with nonlinear specification of age terms. Models with youngest age of interaction from 40 to 70 years, in 1-year increments, were compared, and the best-fitting model for each cognitive measure was chosen. Results across cognitive measures were compared to determine which cognitive indicators showed earliest AD-related change., Results: A total of 405 050 participants (mean [SD] age, 57.1 [7.9] years; 54.1% female) were included. Sample sizes differed across cognitive tests (from 12 455 to 404 682 participants). The AD-GRS significantly modified the association with age on 13 measures derived from the pairs matching (range in difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 2.5%-11.5%), symbol digit substitution (range in difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 2.0%-5.8%), and numeric memory tests (difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 8.8%) (P = 1.56 × 10-3). Best-fitting models suggested that cognitive scores of individuals with a high vs low AD-GRS began to diverge by 56 years of age for all 13 measures and by 47 years of age for 9 measures., Conclusions and Relevance: In this cross-sectional study, by early midlife, subtle differences in memory and attention were detectable among individuals with higher genetic risk of AD.

The relationship between body mass index (BMI) and health outcomes of older adults, including dementia, remains controversial. Many studies find inverse associations between BMI and dementia among older adults, while in other studies high BMI in midlife is associated with increased dementia risk. In this issue, Li et al. (Am J Epidemiol. 2021;190(12):2503-2510) examine BMI from mid- to late life and risk of dementia using the extensive follow-up of the Framingham Offspring Study. They found changing trends in the association between BMI and dementia from a positive association for midlife (ages 40-49) to an inverse trend in late life. Their work demonstrates the importance of studying dementia risk factors across the life course. Midlife obesity might be an important modifiable risk factor for dementia. However, because incipient dementia can lead to weight loss, reverse causation remains a key source of bias that could explain an inverse trend between BMI and dementia in older ages. The extent of other biases, including unmeasured confounding, inaccuracy of BMI as a measure for adiposity, or selective survival, are also unclear. Triangulating evidence on body composition and dementia risk could lead to better targets for dementia intervention, but future work will need to evaluate specific pathways., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Weight loss or lower body mass index (BMI) could be an early symptom of Alzheimer disease (AD), but when this begins to emerge is difficult to estimate with traditional observational data. In an extension of Mendelian randomization, we leveraged variation in genetic risk for late-onset AD risk to estimate the causal effect of AD on BMI and the earliest ages at which AD-related weight loss (or lower BMI as a proxy) occurs. We studied UK Biobank participants enrolled in 2006-2010, who were without dementia, aged 39-73, with European genetic ancestry. BMI was calculated with measured height/weight (weight (kg)/height (m)2). An AD genetic risk score (AD-GRS) was calculated based on 23 genetic variants. Using linear regressions, we tested the association of AD-GRS with BMI, stratified by decade, and calculated the age of divergence in BMI trends between low and high AD-GRS. AD-GRS was not associated with BMI in 39- to 49-year-olds (β = 0.00, 95% confidence interval (CI): -0.03, 0.03). AD-GRS was associated with lower BMI in 50- to 59-year-olds (β = -0.03, 95% CI: -0.06, -0.01) and 60- to 73-year-olds (β = -0.09, 95% CI:-0.12, -0.07). Model-based BMI age curves for high versus low AD-GRS began to diverge after age 47 years. Sensitivity analyses found no evidence for pleiotropy or survival bias. Longitudinal replication is needed; however, our findings suggest that AD genes might begin to reduce BMI decades prior to dementia diagnosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract: Alzheimer disease (AD) is the most common type of dementia characterized by the progressive cognitive and social decline. Clinical drug targets have heavily focused on the amyloid hypothesis, with amyloid beta (Aβ), and tau proteins as key pathophysiologic markers of AD. However, no effective treatment has been developed so far, which prompts researchers to focus on other aspects of AD beyond Aβ, and tau proteins. Additionally, there is a mounting epidemiologic evidence that various environmental factors influence the development of dementia and that dementia etiology is likely heterogenous. In the past decades, new risk factors or potential etiologies have been widely studied. Here, we review several novel epidemiologic and clinical research developments that focus on sleep, hypoxia, diet, gut microbiota, and hearing impairment and their links to AD published in recent years. At the frontiers of AD research, these findings and updates could be worthy of further attention., (Copyright © 2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Topic: Visual impairment (VI) and cognitive impairment (CIM) are prevalent age-related conditions that impose substantial burden on the society. Findings on the hypothesized bidirectional association of VI and CIM remains equivocal. Hence, we conducted a systematic review and meta-analysis to examine this bidirectional relationship., Clinical Relevance: Sixty percent risk of CIM has not been well elucidated in the literature. A bidirectional relationship between VI and CIM may support the development of strategies for early detection and management of risk factors for both conditions in older people., Methods: PubMed, Embase, and Cochrane Central registers were searched systematically for observational studies, published from inception until April 6, 2020, in adults 40 years of age or older reporting objectively measured VI and CIM assessment using clinically validated cognitive screening tests or diagnostic evaluation. Meta-analyses on cross-sectional and longitudinal associations between VI and CIM outcomes (any CIM assessed using screening tests and clinically diagnosed dementia) were examined. Random effect models were used to generate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We also examined study quality, publication bias, and heterogeneity., Results: Forty studies were included (n = 47 913 570). Meta-analyses confirmed that persons with VI were more likely to have CIM, with significantly higher odds of: (1) any CIM (cross-sectional: OR, 2.38 [95% CI, 1.84-3.07]; longitudinal: OR, 1.66 [95% CI, 1.46-1.89]) and (2) clinically diagnosed dementia (cross-sectional: OR, 2.43 [95% CI, 1.48-4.01]; longitudinal: OR, 2.09 [95% CI, 1.37-3.21]) compared with persons without VI. Significant heterogeneity was explained partially by differences in age, sex, and follow-up duration. Also, some evidence suggested that individuals with CIM, relative to cognitively intact persons, were more likely to have VI, with most articles (8/9 [89%]) reporting significantly positive associations; however, meta-analyses on this association could not be conducted because of insufficient data., Discussion: Overall, our work suggests that VI is a risk factor of CIM, although further work is needed to confirm the association of CIM as a risk factor for VI. Strategies for early detection and management of both conditions in older people may minimize individual clinical and public health consequences., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Cancer diagnoses are associated with better long-term memory in older adults, possibly reflecting a range of social confounders that increase cancer risk but improve memory. We used spouse's memory as a negative control outcome to evaluate this possible confounding, since spouses share social characteristics and environments, and individuals' cancers are unlikely to cause better memory among their spouses. We estimated the association of an individual's incident cancer diagnosis (exposure) with their own (primary outcome) and their spouse's (negative control outcome) memory decline in 3601 couples from 1998 to 2014 in the Health and Retirement Study, using linear mixed-effects models. Incident cancer predicted better long-term memory for the diagnosed individual. We observed no association between an individual's cancer diagnosis and rate of spousal memory decline. This negative control study suggests that the inverse association between incident cancer and rate of memory decline is unlikely to be attributable to social/behavioral factors shared between spouses., Competing Interests: K.P.L. and his family member Xiao Zhen Zhou are inventors of cis P-tau antibody technology, which was licensed by BIDMC to the startup Pinteon Therapeutics. K.P.L. and Xiao Zhen Zhou are founders of and own equity in Pinteon. Their interests were reviewed and are managed by BIDMC in accordance with its conflict of interest policy. The remaining authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Preliminary evidence suggests that neighborhood environments, such as socioeconomic disadvantage, pedestrian and physical activity infrastructure, and availability of neighborhood destinations (e.g., parks), may be associated with late-life cognitive functioning and risk of Alzheimer's disease and related disorders (ADRD). The supposition is that these neighborhood characteristics are associated with factors such as mental health, environmental exposures, health behaviors, and social determinants of health that in turn promote or diminish cognitive reserve and resilience in later life. However, observed associations may be biased by self-selection or reverse causation, such as when individuals with better cognition move to denser neighborhoods because they prefer many destinations within walking distance of home, or when individuals with deteriorating health choose residences offering health services in neighborhoods in rural or suburban areas (e.g., assisted living). Research on neighborhood environments and ADRD has typically focused on late-life brain health outcomes, which makes it difficult to disentangle true associations from associations that result from reverse causality. In this paper, we review study designs and methods to help reduce bias due to reverse causality and self-selection, while drawing attention to the unique aspects of these approaches when conducting research on neighborhoods and brain aging.

Background: Amyloid β (Aβ) is thought to initiate a cascade of pathology culminating in Alzheimer's disease-related cognitive decline. Aβ accumulation in brain tissues may begin one to two decades prior to clinical diagnosis of Alzheimer's disease. Prior studies have demonstrated that Aβ detected in vivo with positron emission tomography with amyloid ligands (amyloid-PET) predicts contemporaneously measured cognition and future cognitive trajectories. Prior studies have not evaluated the added value of Aβ measures in predicting future cognition when repeated past cognitive measures are available. We evaluated the extent to which amyloid-PET improves prediction of future cognitive changes over and above predictions based only on sociodemographics and past cognitive measures., Methods: We used data from participants in the University of California Davis Alzheimer's Disease Research cohort who were cognitively normal at baseline, participated in amyloid-PET imaging, and completed at least three cognitive assessments prior to amyloid-PET imaging (N = 132 for memory andN = 135 for executive function). We used sociodemographic and cognitive measures taken prior to amyloid-PET imaging to predict cognitive trajectory after amyloid-PET imaging and assessed whether measures of amyloid burden improved predictions of subsequent cognitive change. Improvements in prediction were characterized as percent reduction in the mean squared error (MSE) in predicted cognition post amyloid-PET and increase in percent variance explained., Results: The base model using only sociodemographics and past cognitive performance explained the majority of variance in both predicted memory measures (55.6%) and executive function measures (74.5%) following amyloid-PET. Adding amyloid positivity to the model reduced the MSE for memory by 0.2%, 95% CI: (0%, 2.6%), p = 0.48 and for executive function by 3.4%, 95% CI: (0.6%, 10.2%), p = 0.002. This corresponded to an increase in the percent variance explained of 0.1%, 95% CI: (0%, 1.2%) for memory and 0.9%, 95% CI: (0.1%, 2.8%) for executive function. Similar results were obtained using a continuous measure of amyloid burden., Conclusion: In this cohort, the addition of amyloid burden slightly improved predictions of executive function compared to models based only on past cognitive assessments and sociodemographics. When repeated cognitive assessments are available, the additional utility of amyloid-PET in predicting future cognitive impairment may be limited., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Depressive symptoms may increase risk for dementia, but findings are controversial because late-life depression may be a prodromal dementia symptom. Life course data on depression and dementia risk may clarify this association; however, data is limited., Objective: To impute adult depressive symptoms trajectories across adult life stages and estimate the association with cognitive impairment and decline., Methods: Using a pooled study of 4 prospective cohorts (ages 20-89), we imputed adult life course depressive symptoms trajectories based on Center for Epidemiologic Studies Depression Scale-10 (CESD-10) and calculated time-weighted averages for early adulthood (ages 20-49), mid-life (ages 50-69), and late-life (ages 70-89) for 6,122 older participants. Adjusted pooled logistic and mixed-effects models estimated associations of imputed depressive symptoms with two cognitive outcomes: cognitive impairment defined by established criteria and a composite cognitive score., Results: In separate models, elevated depressive symptoms in each life stage were associated with cognitive outcomes: early adulthood OR for cognitive impairment = 1.59 (95%CI: 1.35,1.87); mid-life OR = 1.94 (95%CI:1.16, 3.26); and late-life OR = 1.77 (95%CI:1.42, 2.21). When adjusted for depressive symptoms in the other life-stages, elevated depressive symptoms in early adulthood (OR = 1.73; 95%CI: 1.42,2.11) and late-life (OR = 1.43; 95%CI: 1.08,1.89) remained associated with cognitive impairment and were also associated with faster rates of cognitive decline (p < 0.05)., Conclusion: Imputing depressive symptom trajectories from pooled cohorts may help expand data across the life course. Our findings suggest early adulthood depressive symptoms may be a risk factor for cognitive impairment independent of mid- or late-life depressive symptoms.

Growing evidence has suggested an association between sleep duration and Alzheimer's disease (AD), but it is unclear if sleep duration is a manifestation of the AD disease process. We studied whether genetic liability for AD predicts sleep duration using a genetic risk score (GRS) for AD (AD-GRS), in 406,536 UK Biobank participants with European ancestry and without dementia at enrollment. Higher AD-GRS score was associated with shorter sleep (b = -0.014, 95% confidence interval [CI] = -0.022 to -0.006), especially in those aged 55+. Using AD-GRS as an instrumental variable for AD diagnosis, incipient AD reduced sleep duration by 1.87 hours (95% CI = 0.96, 2.78). Short sleep duration might be an early marker of AD. ANN NEUROL 2021;89:177-181., (© 2020 American Neurological Association.)

Objective: To evaluate the association between baseline apathy and probable incident dementia in a population-based sample of community-dwelling older adults., Methods: We studied 2,018 white and black community-dwelling older adults from the Health, Aging, and Body Composition (Health ABC) study. We measured apathy at year 6 (our study baseline) with the modified Apathy Evaluation Scale and divided participants into tertiles based on low, moderate, or severe apathy symptoms. Incident dementia was ascertained over 9 years by dementia medication use, hospital records, or clinically relevant cognitive decline on global cognition. We examined the association between apathy and probable incident dementia using a Cox proportional hazards model adjusting for demographics, cardiovascular risk factors, APOE4 status, and depressed mood. We also evaluated the association between the apathy group and cognitive change (as measured by the modified Mini-Mental State Examination and Digit Symbol Substitution Test over 5 years) using linear mixed effects models., Results: Over 9 years of follow-up, 381 participants developed probable dementia. Severe apathy was associated with an increased risk of dementia compared to low apathy (25% vs 14%) in unadjusted (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.5-2.5) and adjusted models (HR 1.7, 95% CI 1.3-2.2). Greater apathy was associated with worse cognitive score at baseline, but not rate of change over time., Conclusion: In a diverse cohort of community-dwelling adults, apathy was associated with increased risk of developing probable dementia. This study provides novel evidence for apathy as a prodrome of dementia., (© 2020 American Academy of Neurology.)

Importance: Observational studies consistently report inverse associations between cancer and Alzheimer disease (AD). Shared inverse etiological mechanisms might explain this phenomenon, but a systematic evaluation of methodological biases in existing studies is needed., Objectives: To systematically review and meta-analyze evidence on the association between cancer and subsequent AD, systematically identify potential methodological biases in studies, and estimate the influence of these biases on the estimated pooled association between cancer and AD., Data Sources: All-language publications were identified from PubMed, Embase, and PsycINFO databases through September 2, 2020., Study Selection: Longitudinal cohort studies and case-control studies on the risk of AD in older adults with a history of any cancer type, prostate cancer, breast cancer, colorectal cancer, or nonmelanoma skin cancer, relative to those with no cancer history., Data Extraction and Synthesis: Two reviewers independently abstracted the data and evaluated study biases related to confounding, diagnostic bias, competing risks, or survival bias. Random-effects meta-analysis was used to provide pooled estimates of the association between cancer and AD. Metaregressions were used to evaluate whether the observed pooled estimate could be attributable to each bias. The study was designed and conducted according to the Preferring Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline., Main Outcomes and Measures: Incidence, hazard, or odds ratios for AD comparing older adults with vs without a previous cancer diagnosis., Results: In total, 19 cohort studies and 3 case-control studies of the associations between any cancer type (n = 13), prostate cancer (n = 5), breast cancer (n = 1), and nonmelanoma skin cancer (n = 3) with AD were identified, representing 9 630 435 individuals. In all studies combined, cancer was associated with decreased AD incidence (cohort studies: random-effects hazard ratio, 0.89; 95% CI, 0.79-1.00; case-control studies: random-effects odds ratio, 0.75; 95% CI, 0.61-0.93). Studies with insufficient or inappropriate confounder control or greater likelihood of AD diagnostic bias had mean hazard ratios closer to the null value, indicating that these biases could not explain the observed inverse association. Competing risks bias was rare. Studies with greater likelihood of survival bias had mean hazard ratios farther from the null value., Conclusions and Relevance: The weak inverse association between cancer and AD may reflect shared inverse etiological mechanisms or survival bias but is not likely attributable to diagnostic bias, competing risks bias, or insufficient or inappropriate control for potential confounding factors.

Objective: To test the hypothesis that incipient Alzheimer disease (AD) may adversely affect hearing and that hearing loss may adversely affect cognition, we evaluated whether genetic variants that increase AD risk also increase problem hearing and genetic variants that increase hearing impairment risk do not influence cognition., Methods: UK Biobank participants without dementia ≥56 years of age with Caucasian genetic ancestry completed a Digit Triplets Test of speech-in-noise hearing (n = 80,074), self-reported problem hearing and hearing with background noise (n = 244,915), and completed brief cognitive assessments. A genetic risk score for AD (AD-GRS) was calculated as a weighted sum of 23 previously identified AD-related polymorphisms. A genetic risk score for hearing (hearing-GRS) was calculated using 3 previously identified polymorphisms related to hearing impairment. Using age-, sex-, and genetic ancestry-adjusted logistic and linear regression models, we evaluated whether the AD-GRS predicted poor hearing and whether the hearing-GRS predicted worse cognition., Results: Poor speech-in-noise hearing (>-5.5-dB speech reception threshold; prevalence 14%) was associated with lower cognitive scores (ß = -1.28; 95% confidence interval [CI] -1.54 to -1.03). Higher AD-GRS was significantly associated with poor speech-in-noise hearing (odds ratio [OR] 1.06; 95% CI 1.01-1.11) and self-reported problems hearing with background noise (OR 1.03; 95% CI 1.00-1.05). Hearing-GRS was not significantly associated with cognitive scores (ß = -0.05; 95% CI -0.17 to 0.07)., Conclusions: Genetic risk for AD also influences speech-in-noise hearing. We failed to find evidence that genetic risk for hearing impairment affects cognition. AD disease processes or a that shared etiology may cause speech-in-noise difficulty before dementia onset., (© 2020 American Academy of Neurology.)

Introduction: We created a summary score for multiple sensory (multisensory) impairment and evaluated its association with dementia., Methods: We studied 1794 adults aged 70 to 79 who were dementia-free at enrollment and followed for up to 10 years in the Health, Aging, and Body Composition Study. The multisensory function score (0 to 12 points) was based on sample quartiles of objectively measured vision, hearing, smell, and touch summed overall. Risk of incident dementia and cognitive decline (measured by two cognitive tests) associated with the score were assessed in regression models adjusting for demographics and health conditions., Results: Dementia risk was 2.05 times higher (95% confidence interval [CI] 1.50-2.81) comparing "poor" to "good" multisensory score tertiles and 1.45 times higher comparing the "middle" to "good" tertiles (95% CI 1.09-1.91). Each point worse in the multisensory function score was associated with faster rates of cognitive decline (P < .05)., Conclusions: Worsening multisensory function, even at mild levels, was associated with accelerated cognitive aging., (© 2020 the Alzheimer's Association.)

Objective: To examine whether neuropathologic burden is associated with hearing impairment., Methods: We studied 2,755 autopsied participants ≥55 years of age from the National Alzheimer's Coordinating Center database. Participants had at least 1 clinical evaluation at US National Institute on Aging-funded Alzheimer's Disease Center no more than 2 years before death. Patients were classified as hearing impaired by clinician report at baseline. Common dementia neuropathologies included Alzheimer disease pathologic change (Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque density, neurofibrillary degeneration Braak stage), Lewy body disease, gross infarcts, and microinfarcts. Logistic regression models predicted impaired hearing with adjustment for age at death, sex, race, education, center, and follow-up time. Relative risks were calculated with the use of marginal standardization., Results: Impaired hearing was common (32%). In participants who were cognitively normal at baseline (n = 580), impaired hearing was associated with higher Braak stage (relative risk [RR] 1.33 per 2-stage increase, 95% confidence interval [CI] 1.06-1.66) but not other pathologies. In participants with dementia (n = 2,175), impaired hearing was positively associated with microinfarcts (RR 1.18, 95% CI 1.00-1.39) and inversely associated with neuritic plaque density (RR 0.91 per score increase, 95% CI 0.85-0.99). Development of impaired hearing in those with cognitive impairment was associated with neocortical Lewy bodies (1.26, 95% CI 1.02-1.55)., Conclusions: Impaired hearing, reported before the onset of cognitive impairment, was associated with increased neurofibrillary tangle burden. Impaired hearing in those with cognitive impairment was associated with microinfarcts and neocortical Lewy bodies but not typical Alzheimer disease pathologic change. Functional hearing problems may be a preclinical marker of neurofibrillary neurodegeneration, although replication is needed., (© 2020 American Academy of Neurology.)

Introduction: There is limited research on difficulties with activities of daily living (I/ADLs) among older adults living alone with cognitive impairment, including differences by race/ethnicity., Methods: For U.S. Health and Retirement Study (2000-2014) participants aged 55+ living alone with cognitive impairment (4,666 individuals; 9,091 observations), we evaluated I/ADL difficulty and help., Results: Among 4.3 million adults aged 55+ living alone with cognitive impairment, an estimated 46% reported an I/ADL difficulty; 72% reported not receiving help with an I/ADL. Women reported more difficulty than men. Compared to white women, black women were 22% more likely to report a difficulty without help, and Latina women were 36% more likely to report a difficulty with help. Among men, racial/ethnic differences in outcomes were not significant. Patterns of difficulty without help by race/ethnicity were similar among Medicaid beneficiaries., Discussion: Findings call for targeted efforts to support older adults living alone with cognitive impairment., (© 2020 the Alzheimer's Association.)

Introduction: Hearing and vision loss are independently associated with dementia, but the impact of dual sensory impairment (DSI) on dementia risk is not well understood., Methods: Self-reported measures of hearing and vision were taken from 2051 participants at baseline from the Gingko Evaluation of Memory Study. Dementia status was ascertained using standardized criteria. Cox models were used to estimate risk of dementia associated with number of sensory impairments (none, one, or two)., Results: DSI was significantly associated with higher risk of all-cause dementia (hazard ratio [HR] = 1.86; 95% confidence interval [CI] = 1.25-2.76) and Alzheimer's disease (HR = 2.12; 95% CI = 1.34-3.36). Individually only visual impairment was independently associated with an increased risk of all-cause dementia (HR = 1.32; 95% CI = 1.02-1.71)., Discussion: Older adults with DSI are at a significantly increased risk for dementia. Further studies are needed to evaluate whether treatments can modify this risk., (© 2020 the Alzheimer's Association.)

We used differences in state school policies as natural experiments to evaluate the joint influence of educational quantity and quality on late-life physical and mental health. Using US Census microsample data, historical measures of state compulsory schooling and school quality (term length, student-teacher ratio, and attendance rates) were combined via regression modeling on a scale corresponding to years of education (policy-predicted years of education (PPYEd)). PPYEd values were linked to individual-level records for 8,920 black and 14,605 white participants aged ≥45 years in the Reasons for Geographic and Racial Differences in Stroke study (2003-2007). Linear and quantile regression models estimated the association between PPYEd and Physical Component Summary (PCS) and Mental Component Summary (MCS) from the Short Form Health Survey. We examined interactions by race and adjusted for sex, birth year, state of residence at age 6 years, and year of study enrollment. Higher PPYEd was associated with better median PCS (β = 1.28, 95% confidence interval (CI): 0.40, 1.49) and possibly better median MCS (β = 0.46, 95% CI: -0.01, 0.94). Effect estimates were higher among black (vs. white) persons (PCS × race interaction, β = 0.22, 95% CI: -0.62, 1.05, and MCS × race interaction, β = 0.18; 95% CI: -0.08, 0.44). When incorporating both school quality and duration, this quasiexperimental analysis found mixed evidence for a causal effect of education on health decades later., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

It remains unclear what clinical features inform the accuracy of a clinical diagnosis of Alzheimer disease (AD). Data were obtained from the National Alzheimer's Coordinating Center to compare clinical and neuropathologic features among participants who did or did not have Alzheimer disease neuropathologic changes (ADNC) at autopsy. Participants (1854) had a clinical Alzheimer dementia diagnosis and ADNC at autopsy (Confirmed-AD), 204 participants had an AD diagnosis and no ADNC (AD-Mimics), and 253 participants had no AD diagnosis and ADNC (Unidentified-AD). Compared to Confirmed-AD participants, AD-Mimics had less severe cognitive impairment, while Unidentified-AD participants displayed more parkinsonian signs, depression, and behavioral problems. This study highlights the importance of developing a complete panel of biomarkers as a tool to inform clinical diagnoses, as clinical phenotypes that are typically associated with diseases other than AD may result in inaccurate diagnoses., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

A random digit dialing sample from Missouri (USA) was used to compare associations between psychosocial factors and Alzheimer's disease (AD) screening intention based on residential locale. Linear regression associations between demographics and five psychosocial constructs (dementia knowledge, perceived screening benefits, preventive health behaviors, perceived susceptibility, and self-efficacy) and screening intention were compared by residential locale. Participants ( n = 932) had a mean age of 62 years (urban: n = 375; suburban: n = 319, rural: n = 238). African Americans more often lived in urban than suburban/rural neighborhoods, and more urban than suburban/rural residents reported insufficient income. Preventative health behaviors (e.g., dentist visits) were higher in urban and suburban versus rural participants. AD screening intention did not differ by residential locale. Among urban participants, self-efficacy to get screened was associated with screening intention. Among rural participants, dementia knowledge was associated with screening intention. Perceived screening benefits and perceived susceptibility to AD were associated with screening intention regardless of locale. Unlike urban participants, rural participants demonstrated greater screening intention with greater dementia knowledge. Our findings suggest that psychosocial factors associated with AD screening intention differ depending on residential locale. Strategies to increase dementia screening may need to account for regional variations to be maximally effective.

Introduction: Previous studies have provided equivocal evidence of antidepressant use on subsequent cognitive impairment; this could be due to inconsistent modeling approaches. Our goals are methodological and clinical. We evaluate the impact of statistical modeling approaches on the associations between antidepressant use and risk of Mild Cognitive Impairment (MCI) in older adults with depression., Methods: 716 participants were enrolled. Our primary analysis employed a time-dependent Cox proportional hazards model. We also implemented two fixed-covariate proportional hazards models-one based on having ever used antidepressants during follow-up, and the other restricted to baseline use only., Results: Treating antidepressant use as a time-varying covariate, we found no significant association with incident MCI (HR = 0.92, 95% CI: 0.70, 1.20). In contrast, when antidepressant use was treated as a fixed covariate, we observed a significant association between having ever used antidepressants and lower risk of MCI (HR = 0.40, 95% CI: 0.28, 0.56). However, in the baseline-use only model, the association was non-significant (HR = 0.84, 95% CI: 0.60, 1.17)., Discussion: Our results were dependent upon statistical models and suggest that antidepressant use should be modeled as a time-varying covariate. Using a robust time-dependent analysis, antidepressant use was not significantly associated with incident MCI among cognitively normal persons with depression., Competing Interests: The authors have declared that no competing interests exist.

Social support during childhood lays the foundation for social relationships throughout the life course and has been shown to predict a wide range of mental and physical health outcomes. Social support measured in late life is prospectively associated with better cognitive aging, but few studies have evaluated social support received earlier in the life course. We quantified the effects of childhood social support, reported retrospectively, on later-life cognitive trajectories and investigated biopsychosocial mechanisms underlying these associations. Latent growth curve models estimated 10-year cognitive trajectories in 8,538 participants (baseline ages 45-93; M age = 63) in the REasons for Geographic And Racial Differences in Stroke (REGARDS) project. Independent of sociodemographics, childhood socioeconomic status, and household size, greater retrospective childhood social support was associated with better initial episodic memory, but not verbal fluency or cognitive change, in later adulthood. Associations with initial memory level were mediated by sociodemographic and psychosocial variables; specifically, those who reported greater childhood social support reported higher educational attainment and had better physical and emotional health in adulthood, which were each associated with better memory. These results provide support for broad and enduring effects of childhood social support on mental, physical, and cognitive health decades later. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Introduction: Cognitive reserve predicts delayed diagnosis of Alzheimer's disease (AD) and faster postdiagnosis decline. The net impact of cognitive reserve, combining both prediagnosis and postdiagnosis risk, on adverse AD-related outcomes is unknown. We adopted a novel approach, using AD genetic risk scores (AD-GRS), to evaluate this., Methods: Using 242,959 UK Biobank participants age 56+ years, we evaluated whether cognitive reserve (operationalized as education) modified associations between AD-GRS and mortality or hospitalization (total count, fall-related, and urinary tract infection-related)., Results: AD-GRS predicted mortality and hospitalization outcomes. Education did not modify AD-GRS effects on mortality, but had a nonsignificantly (interaction P = .10) worse effect on hospitalizations due to urinary tract infection or falls among low education (OR = 1.07 [95% CI: 1.02, 1.12]) than high education (OR = 1.01 [0.95, 1.07]) individuals., Discussion: Education did not convey differential survival advantages to individuals with higher genetic risk of AD, but may reduce hospitalization risk associated with AD genetic risk., (Copyright © 2019. Published by Elsevier Inc.)

Importance: Patients with a history of cancer, even nonfatal cancers, have lower subsequent Alzheimer disease incidence. An inverse biological link between carcinogenesis and neurodegeneration has been hypothesized, although survival and detection biases are possible explanations., Objective: To compare long-term memory trajectories before and after incident cancer with memory trajectories of similarly aged individuals not diagnosed with cancer., Design, Setting, and Participants: This population-based cohort study included 14 583 US adults born before 1949 with no cancer history from the Health and Retirement Study. Biennial assessments were performed for up to 16 years from 1998 to 2014. Data analysis was performed from January 8 to October 5, 2018., Exposures: Self-reported physician diagnosis of any cancer (excluding nonmelanoma skin cancer) during follow-up., Main Outcomes and Measures: A composite memory score standardized to a mean (SD) of 0 (1) at baseline was based on immediate and delayed word-list recall and proxy assessments. The rate of memory change among people diagnosed with cancer during follow-up before and after diagnosis was compared with rate of memory change in individuals who remained cancer free during follow-up using linear mixed-effect models with random intercepts and slopes., Results: A total of 14 583 participants were included in the sample (mean [SD] age, 66.4 [10.4] years; 8453 [58.0%] female). The mean (SD) follow-up was 11.5 (5.1) years; 2250 had a cancer diagnosis during follow-up, and 12 333 had no cancer diagnosis during follow-up. The rate of memory decline in the decade before a cancer diagnosis was 10.5% (95% CI, 6.2%-14.9%), which was slower than memory decline in similarly aged cancer-free individuals. For individuals diagnosed at 75 years of age, mean memory function immediately before diagnosis was 0.096 SD units (95% CI, 0.060-0.133 SD units) higher compared with that among similarly aged cancer-free individuals. A new cancer diagnosis was associated with a short-term decline in memory of -0.058 (95% CI, -0.084 to -0.032) SD units compared with memory before diagnosis. After diagnosis, the rate of memory decline was 3.9% (95% CI, 0.9%-6.9%) slower in individuals with cancer than in those without a cancer diagnosis., Conclusions and Relevance: In this study, older individuals who developed cancer had better memory and slower memory decline than did similarly aged individuals who remained cancer free. These findings support the possibility of a common pathologic process working in opposite directions in cancer and Alzheimer disease.

Background: Few studies have examined impairment in multiple senses (multisensory impairment) and risk of dementia in comparison to having a single or no sensory impairment., Methods: We studied 1,810 black and white nondemented participants from Health, Aging, and Body Composition (Health ABC) Study aged 70-79 years at enrollment. Sensory impairment was determined at our study baseline (Year 3-5 of Health ABC) using established cut points for vision (Bailey-Lovie visual acuity and Pelli-Robson contrast sensitivity test), hearing (audiometric testing), smell (12-item Cross-Cultural Smell Identification Test), and touch (peripheral nerve function tests). Incident dementia over 10 years of follow-up was based on hospitalization records, dementia medications, or at least 1.5 SD decline in Modified Mini-Mental State Examination score (race-specific). Cox proportional hazard models with adjustment for demographics, health behaviors, and health conditions evaluated the relationship between risk of dementia and increasing number of sensory impairments., Results: Sensory impairments were common: 28% had visual impairment, 35% had hearing loss, 22% had poor smell, 12% had touch insensitivity; 26% had more than two impairments, and 5.6% had more than three sensory impairments. Number of impairments was associated with risk of dementia in a graded fashion (p < .001). Compared to no sensory impairments, the adjusted hazard ratio was 1.49 (95% CI: 1.12, 1.98) for one sensory impairment, 1.91 (95% CI: 1.39, 2.63) for two sensory impairments, and 2.85 (95% CI: 1.88, 4.30) for more than three sensory impairments., Conclusions: Multisensory impairment was strongly associated with increased risk of dementia. Although, the nature of this relationship needs further investigation, sensory function assessment in multiple domains may help identify patients at high risk of dementia., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Thyroid hormone disease is common among older adults and is associated with cognitive impairment. However, pathologic correlates are not well understood. We studied pathologic and clinical factors associated with hypothyroidism, the most common manifestation of thyroid disease, in research subjects seen annually for clinical evaluations at U.S. Alzheimer's Disease Centers. Thyroid disease and treatment status were assessed during clinician interviews. Among autopsied subjects, there were 555 participants with treated hypothyroidism and 2146 without known thyroid disease; hypothyroidism was associated with severe atherosclerosis (odds ratio: 1.35; 95% confidence interval: 1.02, 1.79) but not Alzheimer's disease pathologies (amyloid plaques or neurofibrillary tangles). Among participants who did not undergo autopsy (4598 with treated hypothyroidism and 20,945 without known thyroid hormone disease), hypercholesterolemia and cerebrovascular disease (stroke and/or transient ischemic attack) were associated with hypothyroidism, complementing findings in the smaller autopsy sample. This is the first large-scale evaluation of neuropathologic concomitants of hypothyroidism in aged individuals. Clinical hypothyroidism was prevalent (>20% of individuals studied) and was associated with cerebrovascular disease but not Alzheimer's disease-type neuropathology., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To test whether decline in specific cognitive domains associated with Alzheimer disease neuropathologic change (ADNC) is modified by co-occurrence of other neuropathologies such as Lewy body disease (LBD) or vascular brain injury (VBI)., Methods: Data came from 1,603 autopsied participants evaluated at US Alzheimer's Disease Centers. Standardized z scores in memory, attention, language, and executive function were derived from neuropsychological test scores assessed at each annual visit. Multivariable linear mixed-effects models assessed associations between neuropathologies and longitudinal trajectories of domain scores., Results: Compared to other participants, those with ADNC + LBD generally had worse cognitive trajectories, particularly lower initial executive function and faster attention decline. Participants with ADNC + VBI typically had less impairment and slower decline. Interactions were significant between LBD and ADNC for memory ( p = 0.046) and between VBI and ADNC for language ( p = 0.03); decline was slower than expected if these neuropathologies acted additively on the rate of decline. In secondary models, these interactions were limited to those with high ADNC (but not intermediate ADNC). In a subset of 260 participants with data on microinfarct location, cortical and subcortical microinfarcts were associated with decline in memory, language, and executive function in those without ADNC, but this effect was reduced among those with ADNC., Conclusions: ADNC + LBD (but not ADNC + VBI) was associated with poorer executive function and attention compared to other pathology groupings. However, the effect of co-occurring pathologies on cognitive trajectories may depend on the severity of ADNC. Future studies using antemortem biomarkers should seek to replicate these neuropathologic observations., (© 2017 American Academy of Neurology.)

Introduction: Whether co-occurring neuropathologies interact or independently affect clinical disease progression is uncertain. We estimated rates of clinical progression and tested whether associations between clinical progression and Alzheimer's disease neuropathology (ADNP) were modified by co-occurring Lewy body disease (LBD) or vascular brain injury (VBI)., Methods: Linear mixed effects models evaluated longitudinal trends in the Clinical Dementia Rating Scale Sum of Boxes on 2046 autopsied participants seen at a U.S. Alzheimer's Disease Center., Results: Annual clinical progression was slightly faster for ADNP + LBD compared with ADNP only (P = .06) and slightly slower for ADNP + VBI (P = .003). Differences in progression were less than expected if each neuropathology independently contributed to progression; ADNP interacted with LBD (P = .002) and VBI (P = .003). In secondary models, the effect of additional pathologies on clinical progression was greater in those with intermediate compared with high levels of ADNP., Discussion: The impact of co-occurring pathologies on progression may depend on severity of ADNP., (Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

We examined the relationships between Alzheimer's disease neuropathologic change (ADNC), Lewy body disease (LBD), and vascular brain injury (VBI) in 2 large autopsy samples. Because findings may differ between study populations, data came from U.S. Alzheimer's Disease Centers contributing to the National Alzheimer's Coordinating Center (n = 2742) and from the population-based Adult Changes in Thought study (n = 499). Regardless of study population, over 50% of participants with ADNC had co-occurring LBD or VBI; the majority of whom had a clinical AD dementia diagnosis prior to death. Overlap of pathologies was similar between studies, especially after standardizing to the distribution of age and dementia status in the Adult Changes in Thought population. LBD, but not VBI, was positively associated with ADNC in both studies. Interestingly, cortical LBD was more common in those with intermediate ADNC compared to low or high ADNC, especially in the National Alzheimer's Coordinating Center (p < 0.001). High prevalence of co-occurring neuropathologies among older adults with dementia has implications for accurate diagnosis of dementia etiologies and development of disease-modifying strategies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We examined the relationship between cerebral amyloid angiopathy (CAA), Alzheimer's disease neuropathologic changes, other vascular brain pathologies, and cognition in a large multicenter autopsy sample. Data were obtained from the National Alzheimer's Coordinating Center on autopsied subjects (N = 3976) who died between 2002 and 2012. Descriptive statistics and multivariable regression models estimated the associations between CAA and other pathologies, and between CAA severity and cognitive test scores proximal to death. CAA tended to co-occur with Alzheimer's disease neuropathologic changes but a minority of cases were discrepant. CAA was absent in 22% (n = 520) of subjects with frequent neuritic plaques but present in 20.9% (n = 91) of subjects with no neuritic plaques. In subjects with no/sparse neuritic plaques, nonhemorrhagic brain infarcts were more common in those with CAA pathology than without (p = 0.007). In subjects without the APOE ε4 allele, CAA severity was associated with lower cognition proximal to death, factoring in other pathologies. The presence of CAA in patients without Alzheimer's disease may indicate a distinct cerebrovascular condition., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Although self-rated health (SRH) and performance-based physical function (PPF) are both strong predictors of mortality, little research has investigated the relationships between them. The objective of this study was to evaluate longitudinal, bi-directional associations between SRH and PPF., Methods: We evaluated longitudinal associations between SRH and PPF in 3,610 adults aged 65-89 followed for an average of 4.8 (standard deviation [SD]: 4.4) years between 1994 and July 2011 in the Adult Changes in Thought study, a population-based cohort in the Seattle area. SRH was assessed with a single-item question in the ACT study. Participants were asked at each evaluation to rate their health as "excellent", "very good", "good", "fair", or "poor" in response to the question "In general, how would you rate your health at this time". PPF scores (ranging from 0-16, with higher indicating better performance) included walking speed, chair rises, grip strength, and balance., Results: At the baseline visit, participants averaged 74.5 (SD: 5.8) years of age and 2,115 (58.6%) were female. In multivariable linear mixed models, PPF declined with age, with more rapid decreases associated with very good, good, and fair (vs. excellent) baseline SRH. Adjusted annual change in PPF was -0.17 points (95% confidence interval [CI]: -0.19, -0.15) for individuals with excellent baseline SRH and -0.21 points (95% CI: -0.22, -0.19) for participants with fair SRH. In multivariable generalized linear mixed models, lower baseline PPF quartiles were associated with lower odds of excellent/very good/good SRH at age 75, however, differences between baseline PPF quartiles diminished with age., Conclusions: These results suggest that less than excellent SRH predicts decline in physical functioning, however, poor physical functioning may not predict change in SRH in a reciprocal fashion. SRH provides a simple assessment tool for identifying individuals at increased risk for decline in physical function.

Social relationships are hypothesized to prevent or slow cognitive decline. We sought to evaluate associations between social relationships and mild cognitive impairment (MCI). Participants from the National Alzheimer's Coordinating Center database who were cognitively normal, aged 55 and older at baseline, and had at least 2 in-person visits (n=5335) were included. Multivariable Cox proportional hazard models evaluated the association between 4 social relationships at baseline (marital status, living situation, having children, and having siblings) and risk of developing MCI (on the basis of clinician diagnosis following established criteria). Primary models were adjusted for baseline demographics. Participants were followed, on average, for 3.2 years; 15.2% were diagnosed with MCI. Compared with married participants, risk of MCI was significantly lower for widowed participants (hazard ratio: 0.87; 95% confidence interval: 0.76, 0.99) but not for divorced/separated or never-married participants. Compared with living with a spouse/partner, risk of MCI was significantly higher for living with others (hazard ratio: 1.35; 95% confidence interval: 1.03, 1.77) but not for living alone. Risk of MCI was not associated with having children or having siblings. These results did not consistently identify social relationships as a strong risk factor for, or independent clinical predictor of, MCI.